Somatic Mutations in Tissue and Saliva as Prognostic and Screening Biomarkers for Oral Premalignancy

组织和唾液中的体细胞突变作为口腔癌前病变的预后和筛查生物标志物

• 批准号: 10614548
• 负责人: Nishant Agrawal
• 金额: $ 38.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614548
• 关键词: Biological Markers; Biopsy; Categories; Clinical; Cohort Studies; Collection; Control Groups; Coupled; DNA Sequence Alteration; Detection; Devices; Diagnosis; Diagnostic tests; Disease; Dysplasia; Eligibility Determination; Genes; Goals; Head and Neck Squamous Cell Carcinoma; Health; Histologic; Human; Hyperplasia; Incidence; Inflammatory; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Methods; Modality; Molecular; Morbidity - disease rate; Mutation; Mutation Detection; Oral; Oral Diagnosis; Outcome; Pathogenesis; Patients; Procedures; Prognostic Marker; Research; Retrospective cohort; Saliva; Salivary; Severe dysplasia; Somatic Mutation; Tactile; Testing; Therapeutic; Time; Tissues; United States; Visual; Work; cancer diagnosis; cohort; curative treatments; diagnostic accuracy; driver mutation; high risk; high risk population; improved; innovation; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; next generation sequencing; novel; oral dysplasia; oral lesion; oral premalignancy; oral tissue; population based; premalignant; prognostic; prognostication; risk stratification; saliva sample; screening; targeted sequencing

ABSTRACT Oral cavity squamous cell carcinoma (OCSCC) can be a lethal disease that is often preceded by premalignant lesions, making it is an ideal disease for screening initiatives. However, current screening protocols/tests cannot reliably differentiate between inflammatory and premalignant dysplastic lesions. Further, the histologic diagnosis of dysplasia is an imperfect predictor of malignant transformation as only ~15% of premalignant oral lesions progress to cancer. Our long-term goals are to establish molecular-based diagnostic tests for prognostication and screening that are capable of identifying high-risk patients most likely to progress to oral cancer but would greatly benefit from closer surveillance and less morbid curative intent procedures. Our central hypothesis is that premalignant lesions contain identifiable genetic mutations that can be used for reliable biopsy prognostication (tissue biopsies) and screening (saliva). We will identify dysplasia-specific mutations underlying the pathogenesis of OCSCC. We will validate the mutations identified in a retrospective case-cohort study of dysplastic oral tissues with known clinical outcomes to investigate their potential as tissue-based prognostic biomarkers. We will conduct a case-cohort study using saliva samples from five existing longitudinal population- based United States cohorts to determine whether driver somatic mutations can be identified in saliva prior to the diagnosis of oral cancer. These studies are conceptually innovative and likely to result in state-of-the-art risk stratification and screening. They would be the first to define the functional driver mutations of oral premalignancy. They would also be the first to determine if mutations in driver genes can be detected in saliva prior to oral cancer diagnosis, to define the time-course of mutation detection, and to test the predictive ability of identifying high-risk individuals with somatic mutations. They are technically innovative, as they evaluate the diagnostic accuracy of a novel non-invasive molecular salivary screening platform. This research will benefit human health by improving our ability to identify high-risk premalignant oral lesions likely to progress to cancer, thereby allowing for earlier and potentially more curative interventions with limited morbidity and mortality.

摘要 口腔鳞状细胞癌（OCSCC）可能是一种致命疾病，通常在癌前病变之前出现 病变，使其成为筛查倡议的理想疾病。然而，目前的筛查方案/测试不能 可靠地区分炎性和癌前发育不良病变。此外，组织学诊断 不典型增生是恶性转化的一个不完美的预测因素，因为只有~15%的癌前口腔病变 发展到癌症。我们的长期目标是建立以分子为基础的诊断测试， 和筛查，能够识别最有可能发展为口腔癌的高危患者， 更密切的监测和较少病态的治疗目的程序将大大受益。我们的核心假设是， 癌前病变包含可识别的基因突变，可用于可靠的活检诊断 （组织活组织检查）和筛选（唾液）。我们将识别发育不良特异性突变， OCSCC的发病机制。我们将验证在一项回顾性病例队列研究中发现的突变， 具有已知临床结果的发育不良口腔组织，以研究其作为基于组织的预后评估的潜力。 生物标志物。我们将使用来自五个现有纵向人群的唾液样本进行病例队列研究- 基于美国的队列，以确定是否可以在唾液中识别驱动体细胞突变， 口腔癌的诊断这些研究在概念上具有创新性，可能导致最新风险 分层和筛选。他们将是第一个定义口腔癌基因的功能驱动突变的人。 癌前病变他们也将是第一个确定是否可以在唾液中检测到驱动基因突变的人 在口腔癌诊断之前，确定突变检测的时间过程，并测试 识别具有体细胞突变的高风险个体。他们在技术上是创新的，因为他们评估 新型非侵入性唾液分子筛查平台的诊断准确性。这项研究将有利于 通过提高我们识别可能发展为癌症的高风险癌前口腔病变的能力， 从而允许在发病率和死亡率有限的情况下进行更早和可能更有疗效的干预。

项目成果

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma.

• DOI: 10.3389/fonc.2021.677051
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Broner EC;Trujillo JA;Korzinkin M;Subbannayya T;Agrawal N;Ozerov IV;Zhavoronkov A;Rooper L;Kotlov N;Shen L;Pearson AT;Rosenberg AJ;Savage PA;Mishra V;Chatterjee A;Sidransky D;Izumchenko E
• 通讯作者: Izumchenko E

Ultrasensitive detection of tumor-specific mutations in saliva of patients with oral cavity squamous cell carcinoma.

• DOI: 10.1002/cncr.33393
• 发表时间: 2021-05-15
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Shanmugam A;Hariharan AK;Hasina R;Nair JR;Katragadda S;Irusappan S;Ravichandran A;Veeramachaneni V;Bettadapura R;Bhati M;Ramaswamy V;Rao VUS;Bagadia RK;Manjunath A;Manjunath NML;Solomon MC;Maji S;Bahadur U;Bettegowda C;Papadopoulos N;Lingen MW;Hariharan R;Gupta V;Agrawal N;Izumchenko E
• 通讯作者: Izumchenko E

Microbial Changes Associated With Oral Cavity Cancer Progression.

• DOI: 10.1002/ohn.211
• 发表时间: 2023-06
• 期刊: OTOLARYNGOLOGY-HEAD AND NECK SURGERY
• 影响因子: 3.4
• 作者: Yan, Kenneth;Auger, Samuel;Diaz, Ashley;Naman, Julia;Vemulapalli, Ramya;Hasina, Rifat;Izumchenko, Evgeny;Shogan, Benjamin;Agrawal, Nishant
• 通讯作者: Agrawal, Nishant

AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling.

• DOI: 10.1038/s41419-022-05133-9
• 发表时间: 2022-08-05
• 期刊: CELL DEATH & DISEASE
• 影响因子: 9
• 作者: Ferrarotto, Renata;Mishra, Vasudha;Herz, Elad;Yaacov, Adar;Solomon, Oz;Rauch, Rami;Mondshine, Adi;Motin, Maria;Leibovich-Rivkin, Tal;Davis, Matti;Kaye, Joel;Weber, Christopher R.;Shen, Le;Pearson, Alexander T.;Rosenberg, Ari J.;Chen, Xiangying;Singh, Alka;Aster, Jon C.;Agrawal, Nishant;Izumchenko, Evgeny
• 通讯作者: Izumchenko, Evgeny

A robust and interpretable gene signature for predicting the lymph node status of primary T1/T2 oral cavity squamous cell carcinoma.

• DOI: 10.1002/ijc.33828
• 发表时间: 2022-02-01
• 期刊: International journal of cancer
• 影响因子: 6.4
• 作者: Ghantous Y;Omar M;Broner EC;Agrawal N;Pearson AT;Rosenberg AJ;Mishra V;Singh A;El-Naaj IA;Savage PA;Sidransky D;Marchionni L;Izumchenko E
• 通讯作者: Izumchenko E